The present invention relates to an apparatus and method for reducing interstitial fluid pressure, enhancing radiation therapy, and enhancing delivery and effectiveness of therapeutic agents in tissue, particularly in tumors.
Throughout this application various publications are referenced and citations are provided in the Reference section. The disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Cancer is the second leading cause of death in this country and still continues to be a public health problem of increasing significance.1 Cancer therapy may be categorized into three major approaches: surgical excision, radiotherapy, and chemotherapy. Chemotherapy is defined as the treatment of cancer by a systemic administration of drugs.
Unfortunately, most drugs which showed promising effects in vitro have failed to be as effective in vivo, particularly in solid tumors. It has been proposed that one of the major reasons for this failure is the impediment of drug transport into tumors. In particular, a physiological barrier created by raised interstitial fluid pressure appears to be responsible. The interstitial fluid pressure is raised in tumors primarily because of the lack of lymphatics in tumors and growth of tumor cells in confined spaces. The raised interstitial fluid pressure in tumors is a principal transport-retarding factor for the delivery of drugs such as macromolecules, i.e., large molecular weight molecules such as monoclonal antibodies (MoAb), tumor necrosis factor, and other chemotherapeutic agents.
Jain et al. suspected that elevated interstitial fluid pressure is a principal transport retarding factor in MoAb delivery because of the lack of lymphatics in the tumor.2,3 In normal tissue, maintenance of the fluid balance within the tissue spaces is dependent upon the interplay of hydrostatic and colloid osmotic pressures operating on a vascular network with uneven permeability and with dissimilar exchange area with the aid of the lymphatic system. The lymphatics are responsible for returning extravasated fluids and macromolecules to circulation throughout the body. Most macromolecules, including proteins, cannot return to circulation without the lymphatic system after they percolate through the endothelial wall.4 Accordingly, lymphatic drainage is a factor of primary importance in maintaining fluid balance.5 Once the equilibrium is disrupted, dehydration or edema in the tissue would result from the imbalanced colloid osmotic and hydrostatic vascular pressure. These relations are well described by Starling""s hypothesis.6 
A functioning lymphatic system as an anatomical entity has not been demonstrated in the tumor. The absence of lymphatics affords no alternative way by which macromolecules can re-enter the circulation after their extravasation through the capillaries. The potential of fluid flow into the tumor is hindered by an opposing force with equivalent magnitude from interstitial fluid pressure. This opposing force increases until all the forces in Starling""s Law are balanced. The convective component of drug transport from capillary to interstitial space is blocked and the predominant mechanism is molecular diffusion. Fluid oozes out toward the tumor surface because of the lower effective pressure at the tumor periphery resulting from draining advantage by lymphatics of the normal tissue at the tumor periphery. This outward fluid velocity from the tumor center to the tumor periphery additionally hinders the diffusional movement of treatment molecules into the tumor center.2 Decreased intravascular pressure and/or increased interstitial pressure in tumors has been demonstrated by several investigators.7-12 
Findings to date indicate that elevated interstitial fluid pressure has been attributed to the absence of a well-defined lymphatic system in the tumor,3, 13 and to increased permeability of tumor vessels.14, 15 Researchers reported that interstitial fluid pressure increases with tumor size.16-19 The increase in interstitial fluid pressure has also been shown to correlate with reduction in tumor blood flow (lower blood perfusion rate) and the development of necrosis in a growing tumor.16-18, 20 
Jain et al. presented a mathematical model describing the possible relationship between the distribution of macromolecules, e.g., monoclonal antibodies (MoAbs) and elevated interstitial pressure.21 They proposed that increased interstitial fluid pressure might be responsible for the poor penetration of MoAbs into tumors including the heterogeneous blood perfusion, hindered diffusion in the interstitium, and extravascular binding of MoAbs. Furthermore, they stated that the elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and leads to an experimentally verifiable, radially outward convection which opposed the inward diffusion. They have presented results from several mathematical models and the models"" implications to support their hypothesis.2, 3, 22, 23 
A variety of approaches have been tried to enhance delivery of therapeutic agents to tumors. For example, U.S. Pat. No. 5,484,399 to DiResta et al. (xe2x80x9cDiResta ""399 patentxe2x80x9d), the contents of which are incorporated herein by reference, discloses a process and device to reduce interstitial fluid pressure in tissue. Briefly, the DiResta ""399 patent discloses an artificial lymphatic system (ALS) which includes a plurality of aspiration tubes, each having a plurality of aspiration holes, and a manifold for connecting the tubes to a vacuum source. Experimental studies have shown that the ALS has resulted in reduced interstitial fluid pressure within tumors, increased blood flow within tumors, and enhanced uptake of chemotherapeutic drugs into the tumors. Specifically, by reducing interstitial fluid pressure, blood flow, pH, and pO2 all increase to more normal levels. These changes increase delivery of drugs to the tissue and drug uptake into the cells. The increase in tissue pH enhances the reaction kinetics of drugs whose pH optimum is in the normal range. Increasing pO2 enhances radiation therapy because oxygen is the most potent radiationsensitizing agent currently known.
Despite these promising findings, there are limitations to the ALS. Specifically, the small holes in the ALS may tend to become blocked with time. As a result, long term use of the ALS could potentially be problematic. Long term use of the ALS may further be complicated by the lack of a mechanism to secure the drains of the ALS to the tissue so that the drains remain spatially fixed. Finally, the ALS had no features that facilitate use with adjunct therapies that enhance drug delivery. Use of various other therapies to enhance efficacy of the ALS would be desirable. However, until now, no other adjunct therapy has been used in conjunction with the ALS.
Electroporation is another therapy that has been used to enhance delivery of therapeutic agents to tumors. Recent studies have demonstrated that electroporation may be beneficial in the treatment of accessible solid tumors. Electroporation is a technique that uses pulsed electric fields to create transient pores within cell membranes to temporarily increase the membrane""s permeability to exogenous molecular agents. The electric fields are created between pairs of needle electrodes inserted into a tissue region of interest. The electrode separation distance is typically fixed and a grid array of electrodes is used to treat tissue regions.
As electroporation requires that the desired drugs be within the tissue region to be treated when the electric field is induced, the major problem with the successful use of electroporation is the need for an adequate quantity of the therapeutic agent in the region at which the electric field will be generated. Blood flow is low in many solid tumors and thus drugs administered via intravenous or intra-arterial routes frequently do not enter the tumor in cytotoxic concentrations. As an alternative, intra-tumoral injections are used to deliver the drugs directly into the tumor regions scheduled for electroporation to avoid the transport problems. However, the drug distribution from intra-tumoral injection is non-uniform and the technique requires multiple injections with fan motions that may damage the tissue.
As previously indicated, low tumor blood flow results from the existence of elevated interstitial fluid pressure within the tumor. The physiological basis cited to explain this phenomena includes the tumor""s xe2x80x9cleakyxe2x80x9d capillaries and lack of a functioning lymphatic system to drain the excess fluid that accumulates within the interstitial spaces. The elevated interstitial fluid pressure throttles the blood flow that delivers drug to tumors. In addition, the elevated interstitial fluid pressure reduces the convective component of drug movement from the capillaries into the interstitial spaces. As a result, drug movement proceeds via diffusion, a much slower process. It would be advantageous to use a system, such as the ALS, in conjunction with electroporation so that drug delivery is enhanced. However, as the ALS was not designed for use with electroporation, their simultaneous use is not straightforward.
Thus, there exists a need for an improved apparatus and process for reducing interstitial fluid pressure and enhancing delivery of a therapeutic agent.
The present invention relates to an interstitial fluid pressure reducing apparatus that includes an aspiration probe having a body with an open proximal end and a closed distal end, an interior chamber defined by the body and proximal and distal ends, and at least one slit along the body providing fluid communication between the chamber of the aspiration probe and tissue upon insertion of at least a portion of the aspiration probe in tissue. The proximal end is configured and dimensioned for coupling to a suction source for generating suction in the chamber of the aspiration probe upon connection with the aspiration probe to thereby reduce interstitial fluid pressure of the tissue.
In order to secure the aspiration probe to tissue, the aspiration probe can have a suture ring at the proximal end. In one embodiment, at least one hole is defined in the suture ring shaped to receive a suture. The apparatus can include a connection member having a first end configured and dimensioned for removably connecting with the proximal end of the aspiration probe and a second end configured and dimensioned for removably connecting with the suction source.
The apparatus optionally includes other components. One such component is a cleaning obturator configured and dimensioned for sliding movement into the chamber through the proximal end of the aspiration probe. The cleaning obturator has at least one fin engaging at least one slit upon insertion of the cleaning obturator into the chamber for removing any debris from the slit.
A blocking obturator can also be a component of the apparatus. The blocking obturator is configured and dimensioned to fit within the chamber to block at least one slit. As a result, fluid communication between the chamber of the aspiration probe and tissue is blocked to prevent accumulation of tissue or debris in the chamber. The blocking obturator can have at least one rib configured and dimensioned to block at least one slit.
The apparatus can also include a conducting obturator configured and dimensioned for sliding movement into the chamber. The conducting obturator is made of an electrically conductive material for serving as an electrode for electroporation. In one embodiment, at least a portion of the aspiration probe is made of an electrically conductive material for serving as an electrode for electroporation.
The present invention also relates to an interstitial fluid pressure reducing apparatus comprising an aspiration probe having a body with an open proximal end and a closed distal end, an interior chamber defined by the body and proximal and distal ends, and a plurality of apertures along the body providing fluid communication between the chamber of the aspiration probe and tissue upon insertion of at least a portion of the aspiration probe in tissue. The proximal end is configured and dimensioned for coupling with a suction source for generating suction in the chamber of the aspiration probe upon connection with the aspiration probe to thereby reduce interstitial fluid pressure of the tissue. The apparatus further comprises a cleaning obturator configured and dimensioned for sliding movement into the chamber through the proximal end of the aspiration probe. The cleaning obturator has at least one protrusion engaging the plurality of apertures upon insertion of the cleaning obturator into the chamber for removing any debris from the plurality of apertures.
The present invention also relates to an interstitial fluid pressure reducing apparatus comprising an aspiration probe having a body with an open proximal end and a closed distal end, an interior chamber defined by the body and proximal and distal ends, and a plurality of apertures along the body providing fluid communication between the chamber of the aspiration probe and tissue upon insertion of at least a portion of the aspiration probe in tissue. The proximal end is configured and dimensioned for coupling with a suction source for generating suction in the chamber of the aspiration probe upon connection with the aspiration probe to thereby reduce interstitial fluid pressure of the tissue. The apparatus further comprises a blocking obturator configured and dimensioned to fit within the chamber to block the plurality of apertures thereby blocking the fluid communication between the chamber of the aspiration probe and tissue for preventing accumulation of tissue or debris in the chamber. The blocking obturator can be impregnated with a therapeutically effective amount of a pharmacological agent, such as an antibiotic. In one embodiment, the blocking obturator is made of a biocompatible polymer, such as polymethyl methacrylate. At least a portion of the blocking obturator can be made of an electrically conductive material for serving as an electrode for electroporation.
The present invention also relates to a system for reducing interstitial pressure of tissue. The system comprises at least two aspiration probes, each having a body with an open proximal end and a closed distal end, an interior chamber defined by the body and proximal and distal ends, and at least one slit along the body providing fluid communication between the chamber of the aspiration probe and tissue upon insertion of at least a portion of the aspiration probe in tissue. A suction source generates suction in the chamber of each of the aspiration probes upon connection with the respective aspiration probe to thereby reduce interstitial fluid pressure of the tissue. The system also includes a plurality of connection members, each having a first end configured and dimensioned for removably connecting with the proximal end of one of the aspiration probes and a second end configured and dimensioned for removably connecting with the suction source. A manifold having a suction source port removably connects with the suction source and a plurality of aspiration probe ports, each for removably connecting with one of the connection members. Each of the aspiration probes can have a separately adjustable vacuum pressure.
The system can include a chamber defined in the manifold in fluid communication with each of the aspiration probe ports for collection of aspirated fluid. The system can also include a valve operatively associated with each of the aspiration probe ports for selective coupling and uncoupling of the aspiration probe port to the suction source. A plurality of chambers can be defined in the manifold. Each chamber is in fluid communication with one of the aspiration probe ports for collection of aspirated fluid. Additionally, a valve is operatively associated with the suction source port for selective coupling and uncoupling to the suction source. The valve allows retention of pressure generated by the suction source upon uncoupling with the suction source. In this embodiment, at least a portion of the manifold can be implantable. The system can optionally include other components such as a cleaning obturator configured and dimensioned for sliding movement into the chamber through the proximal end of one of the aspiration probe. The cleaning obturator has at least one fin engaging at least one slit upon insertion of the cleaning obturator into the chamber for removing any debris from the slit. The system can also include at least one drug delivery probe having a body with an open proximal end and a closed distal end, an interior chamber defined by the body and proximal and distal ends, and at least one slit along the body providing fluid communication between the chamber of the drug delivery probe and tissue upon insertion of at least a portion of the drug delivery probe in tissue. At least a portion of at least one of the aspiration probes can be made of an electrically conductive material for serving as an electrode for electroporation.
The present invention also relates to a method for reducing interstitial fluid pressure of tissue comprising the steps of: implanting at least a portion of an aspiration probe in tissue; coupling the aspiration probe to a suction source to generate suction in the aspiration probe and thereby reduce interstitial fluid pressure of tissue; and cleaning the aspiration probe to remove debris. At least a portion of the aspiration probe remains implanted in tissue when the aspiration probe is cleaned. The method can also include the step of inserting a blocking obturator in the aspiration probe when suction is not applied to prevent debris from accumulating in the aspiration probe. Furthermore, the suction source can selectively be turned on and off or adjusted to different levels to generate a pressure field to assist in delivery and distribution of a pharmacological agent to tissue regions.
The present invention also relates to another method for reducing interstitial fluid pressure of tissue. At least a portion of at least two aspiration probes is implanted in tissue. At least one of the aspiration probes is coupled to a suction source to generate suction and thereby reduce interstitial fluid pressure of tissue. Drug is delivered to the tissue and the delivery of the drug is assisted with electroporation. At least a portion of at least one of the aspiration probes is made of electrically conductive material for serving as an electrode for the electroporation. In one embodiment, suction and electroporation occur simultaneously.